Chemoprotectants for Head-Neck Therapeutics Oral mucositis occurs as a major dose-limiting and complicating side effect of chemotherapy, radiotherapy, or combined chemo/radiotherapy. It is considered the most significant complication of head and neck cancer therapy. Oral mucositis is accompanied by tremendous pain and can cause life threatening complications. Dysfunction in swallowing following laryngeal cancer therapy can be particularly debilitating. The development of chemoprotectants is the central goal of this proposal. In preliminary studies, Reaction Biology Corporation has discovered selective, reversible, small molecule caspase inhibitors, which have multiple advantages compared to the compounds in the clinical trials. For example, caspase inhibitors from many pharmaceutical companies' drug discovery programs have one of more of the following characteristics: irreversible, peptide-mimic, Pan-caspase inhibitor. In Phase I studies, these compounds are very active in cell based assays, demonstrated significant cell death prevention activities in chemical and radiation induced cell death in normal cell lines. In this Phase II application, we will continue to improve these inhibitors in potency and efficacy in cell based assays and DMPK profiles, to look for the final lead(s) in animal model tests. In this new proposal, the key aims are: 1) Structure-Activity Relationship (SAR) studies to improve caspase inhibitors' potency; 2) Define caspase inhibitors' treatment conditions in vitro in conjugation with chemotherapy and radiation treatments; 3) Test caspase inhibitors' tissue penetration and efficacy in protecting oral mucous cells from radiation therapy in 3D oral mucosa model.